CENTER FOR DRUG EVALUATION AND
`RESEARCH
`APPLICATION NUMBER:
`206073Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`
`
`
`

`

`NDA-206073
`Sponsor: Boehringer Ingelheim
`SD-1, eCTD-0000
`Received: January 29, 2014
`Primary Safety Review/CDTL
`Reviewer: William H. Chong
`
`
`
`CLINICAL REVIEW/CROSS-DISCIPLINE TEAM LEADER REVIEW
`
`
`
`Application NDA-206073
`Supporting Document Number SD-1
`
`
`Submission Receipt Date January 29, 2014
`PDUFA Goal Date January 30, 2015
`Division Division of Metabolism and Endocrinology
`Products
`
`
`Reviewer William H. Chong
`Review Completion Date January 29, 2015
`
`
`Generic name Empagliflozin/Linagliptin
`Trade name GLYXAMBI
`Therapeutic class Fixed dose combination of a sodium dependent
`glucose cotransporter-2 inhibitor and a
`dipeptidyl peptidase-4 inhibitor
`Applicant Boehringer Ingelheim
`Priority designation Standard
`
`
`Formulation Tablet
`Dosing regimen Empagliflozin 10 mg/Linagliptin 5 mg
`Empagliflozin 25 mg/Linagliptin 5 mg
`Indication Type 2 diabetes mellitus
`Intended population Adults with type 2 diabetes mellitus
`
`
`Related INDs/NDAs IND-108388 (Empagliflozin/Linagliptin);
`NDA-201280 (Linagliptin); NDA-204629
`(Empagliflozin)
`
`
`Division Director Jean-Marc Guettier
`Statistical Reviewer Jennifer Clark
`Clinical Pharmacology Reviewer Suryanarayana Sista
`Pharmacology/Toxicology Reviewer David Carlson
`Chemistry, Manufacturing and Controls Joseph Leginus and Kareen Riviere
`Project Manager Callie Cappel-Lynch
`
`Reference ID: 3694050
`
`

`

`NDA-206073 (Empagliflozin/Linagliptin)
`Initial NDA Submission
`Clinical Review and Cross-Discipline Team Leader Review
`Reviewer: William H. Chong
`
`
`
`
`Table of Contents
`
`Table of Contents ............................................................................................................................ 2
`Table of Tables ............................................................................................................................... 6
`Table of Figures ............................................................................................................................ 10
`Abbreviations: ............................................................................................................................... 11
`1. Recommendations/Risk-Benefit Assessment ........................................................................ 13
`1.1 Recommendation on Regulatory Action ........................................................................ 13
`1.2 Risk-Benefit Assessment ................................................................................................ 13
`1.3 Recommendations for Post market Risk Evaluation and Mitigation Strategies ............ 17
`1.4 Recommendations for Post market Requirements and Commitments ........................... 17
`2.
`Introduction and Regulatory Background ............................................................................. 17
`2.1
`Product information ........................................................................................................ 17
`2.2 Currently Available Treatments for the Proposed Indication ........................................ 17
`2.3 Availability of Proposed Active Ingredient in the United States ................................... 18
`2.4
`Important Issues with Consideration to Related Drugs .................................................. 18
`2.5
`Summary of Presubmission Regulatory Activity Related to Submission ...................... 18
`3. Ethics and Good Clinical Practices ....................................................................................... 19
`3.1
`Submission Quality and Integrity ................................................................................... 19
`3.2 Compliance with Good Clinical Practice ....................................................................... 19
`3.3
`Financial Disclosures ..................................................................................................... 19
`4. Significant Efficacy/Safety Issues Related to Other Review Disciplines ............................. 19
`4.1 Chemistry, Manufacturing and Controls ........................................................................ 19
`4.2 Clinical Microbiology .................................................................................................... 21
`4.3
`Preclinical Pharmacology/Toxicology ........................................................................... 21
`4.4 Clinical Pharmacology ................................................................................................... 23
`4.4.1 Mechanisms of Action ............................................................................................ 23
`4.4.2
`Pharmacodynamics ................................................................................................. 23
`4.4.3
`Pharmacokinetics .................................................................................................... 23
`5. Sources of Clinical Data ........................................................................................................ 24
`5.1
`Tables of Studies/Clinical Trials .................................................................................... 25
`5.2 Review Strategy ............................................................................................................. 25
`5.3 Discussion of Individual Studies/Clinical Trials ............................................................ 26
`6. Review of Efficacy ................................................................................................................ 26
`6.1
`Efficacy Summary .......................................................................................................... 26
`
`Reference ID: 3694050
`
`
`2
`
`

`

`NDA-206073 (Empagliflozin/Linagliptin)
`Initial NDA Submission
`Clinical Review and Cross-Discipline Team Leader Review
`Reviewer: William H. Chong
`
`
`Indication ........................................................................................................................ 28
`6.2
`6.2.1 Methods................................................................................................................... 28
`6.2.2
`Demographics ......................................................................................................... 28
`6.2.3
`Patient Disposition .................................................................................................. 29
`6.2.4
`Analysis of Primary Endpoint(s) ............................................................................ 33
`6.2.5
`Analysis of Secondary Endpoint(s) ........................................................................ 35
`6.2.5.1
`Fasting plasma glucose .................................................................................... 35
`6.2.5.2
`Body weight ..................................................................................................... 37
`6.2.5.3
`Ability to achieve target HbA1c ...................................................................... 39
`6.2.6
`Other Endpoint(s).................................................................................................... 41
`6.2.6.1
`Changes in blood pressure ............................................................................... 41
`6.2.6.2
`Need for rescue medication ............................................................................. 47
`6.2.7
`Subpopulations ........................................................................................................ 49
`6.2.7.1
`By baseline HbA1c .......................................................................................... 49
`6.2.7.2
`By Age ............................................................................................................. 54
`6.2.7.3
`By estimated glomerular filtration rate ............................................................ 57
`6.2.7.4
`By region ......................................................................................................... 60
`6.2.8
`Analysis of Clinical Information Relevant to Dosing Recommendations .............. 63
`6.2.9
`Discussion of Persistence of Efficacy and/or Tolerance Effects ............................ 63
`6.2.10 Additional Efficacy Analyses ................................................................................. 65
`6.2.11 Discussion of Efficacy Issue(s) ............................................................................... 66
`7. Review of Safety ................................................................................................................... 67
`7.1
`Safety Summary ............................................................................................................. 67
`7.2 Methods .......................................................................................................................... 68
`7.2.1
`Studies/Clinical Trials Used to Evaluate Safety ..................................................... 68
`7.2.2
`Categorization of Adverse Events .......................................................................... 68
`7.2.2.1
`Criteria for Withdrawal/Early Discontinuation ............................................... 69
`7.2.3
`Pooling of Data Across Clinical Trials to Estimate and Compare Incidence ......... 70
`7.3 Adequacy of Safety Assessments ................................................................................... 70
`7.3.1
`Overall Exposure at Appropriate Doses/Durations and Demographics of Target
`Populations ............................................................................................................................ 70
`7.3.2
`Explorations for Dose Response ............................................................................. 74
`Special Animal and/or In Vitro Testing .................................................................. 74
`7.3.3
`7.3.4
`Routine Clinical Testing ......................................................................................... 74
`7.3.5 Metabolic, Clearance, and Interaction Workup ...................................................... 74
`7.3.6
`Evaluation for Potential Adverse Events for Similar Drugs in Drug Class ............ 74
`
`Reference ID: 3694050
`
`
`3
`
`

`

`NDA-206073 (Empagliflozin/Linagliptin)
`Initial NDA Submission
`Clinical Review and Cross-Discipline Team Leader Review
`Reviewer: William H. Chong
`
`
`7.4 Major Safety Results ...................................................................................................... 75
`7.4.1
`Deaths ..................................................................................................................... 75
`7.4.1.1
`Narratives of Deaths ........................................................................................ 76
`7.4.2
`Nonfatal Serious Adverse Events ........................................................................... 79
`7.4.2.1
`Narratives of Non-fatal Serious Adverse Events ............................................. 80
`7.4.3
`Dropouts and/or Discontinuations .......................................................................... 83
`7.4.3.1
`Narratives of Discontinuations due to Adverse Events ................................... 85
`7.4.4
`Significant Adverse Events ..................................................................................... 85
`7.4.5
`Submission Specific Safety Concerns .................................................................... 88
`7.4.5.1
`Volume depletion ............................................................................................ 88
`7.4.5.2
`Changes in renal function .............................................................................. 100
`7.4.5.3
`Hepatic events ................................................................................................ 102
`7.4.5.4
`Urinary tract infections .................................................................................... 91
`7.4.5.5
`Genital infections ............................................................................................. 94
`7.4.5.6 Malignancies .................................................................................................. 100
`7.4.5.7
`Hypoglycemia .................................................................................................. 88
`7.4.5.8
`Pancreatitis..................................................................................................... 107
`7.4.5.9
`Hypersensitivity reactions ............................................................................. 107
`7.4.5.10
`Skin lesions .................................................................................................... 108
`7.4.5.11 Cardiovascular Safety .................................................................................... 110
`Supportive Safety Results ............................................................................................ 112
`7.5
`7.5.1
`Common Adverse Events ..................................................................................... 112
`7.5.2
`Laboratory Findings .............................................................................................. 124
`7.5.2.1
`Electrolytes .................................................................................................... 124
`7.5.2.2
`Lipase............................................................................................................. 125
`7.5.2.3
`Hematocrit ..................................................................................................... 128
`7.5.2.4
`Lipids ............................................................................................................. 131
`7.5.3
`Vital Signs ............................................................................................................. 135
`7.5.4
`Electrocardiograms ............................................................................................... 136
`7.5.5
`Special Safety Studies/Clinical Trials ................................................................... 136
`7.5.6
`Immunogenicity .................................................................................................... 136
`7.6 Other Safety Explorations ............................................................................................ 136
`7.6.1
`Dose Dependency for Adverse Events ................................................................. 136
`7.6.2
`Time Dependency for Adverse Events ................................................................. 136
`7.6.3
`Drug-Demographic Interactions ........................................................................... 136
`7.6.4
`Drug-Disease Interactions ..................................................................................... 137
`
`Reference ID: 3694050
`
`
`4
`
`

`

`NDA-206073 (Empagliflozin/Linagliptin)
`Initial NDA Submission
`Clinical Review and Cross-Discipline Team Leader Review
`Reviewer: William H. Chong
`
`
`Drug-Drug Interactions ......................................................................................... 137
`7.6.5
`7.7 Additional Safety Evaluations ...................................................................................... 137
`7.7.1
`Human Carcinogenicity ........................................................................................ 137
`7.7.2
`Human Reproduction and Pregnancy Data ........................................................... 137
`7.7.3
`Pediatrics and Assessment of Effects on Growth ................................................. 137
`7.7.4
`Overdose, Drug Abuse Potential, Withdrawal, and Rebound .............................. 137
`7.8 Additional Submission/Safety Issues ........................................................................... 137
`8. Post marketing Experience .................................................................................................. 138
`9. Appendices .......................................................................................................................... 138
`9.1
`Labeling Recommendations ......................................................................................... 138
`9.2 Advisory Committee Meeting ...................................................................................... 138
`9.3
`Financial Disclosures Template(s) ............................................................................... 139
`9.4
`Lists of preferred terms ................................................................................................ 141
`9.5 Reviewer generated adverse event tables ..................................................................... 143
`
`Reference ID: 3694050
`
`
`5
`
`

`

`NDA-206073 (Empagliflozin/Linagliptin)
`Initial NDA Submission
`Clinical Review and Cross-Discipline Team Leader Review
`Reviewer: William H. Chong
`
`
`
`Table of Tables
`
`Table 1: Studies submitted in support of the New Drug Application ........................................... 25
`Table 2: Treatment arms by patient population ............................................................................ 26
`Table 3: Distribution of patients by treatment .............................................................................. 29
`Table 4: Disposition of patients at 24 weeks – randomized set .................................................... 31
`Table 5: Disposition of patients at 52 weeks – randomized set .................................................... 32
`Table 6: Change in HbA1c from baseline at 24 weeks for metformin patients ............................ 34
`Table 7: Difference between treatments for HbA1c at 24 weeks for metformin patients ............ 34
`Table 8: Change in HbA1c from baseline at 24 weeks for treatment naive ................................. 34
`Table 9: Difference between treatments for HbA1c at 24 weeks for treatment naive .................. 35
`Table 10: Change in fasting plasma glucose from baseline at 24 weeks for metformin patients . 36
`Table 11: Difference between treatments for fasting plasma glucose at 24 weeks for metformin
`patients .......................................................................................................................................... 36
`Table 12: Change in fasting plasma glucose from baseline at 24 weeks for treatment naive ...... 37
`Table 13: Difference between treatments for fasting plasma glucose at 24 weeks for treatment
`naive .............................................................................................................................................. 37
`Table 14: Change in body weight from baseline at 24 weeks for metformin patients ................. 38
`Table 15: Difference between treatments for body weight at 24 weeks for metformin patients .. 38
`Table 16: Change in body weight from baseline at 24 weeks for treatment naïve ....................... 39
`Table 17: Difference between treatments for body weight at 24 weeks for treatment naïve ....... 39
`Table 18: Ability to achieve an HbA1c < 7% if baseline HbA1c ≥ 7% - full analysis set, non-
`completers considered failure, metformin patients ....................................................................... 40
`Table 19: Ability to achieve an HbA1c < 7% if baseline HbA1c ≥ 7% - full analysis set, non-
`completers considered failure, treatment naive ............................................................................ 40
`Table 20: Adjusted mean change in systolic blood pressure – full analysis set, last observation
`carried forward, metformin patients ............................................................................................. 42
`Table 21: Adjusted mean change in diastolic blood pressure – full analysis set, last observation
`carried forward, metformin patients ............................................................................................. 43
`Table 22: Adjusted mean change in systolic blood pressure – full analysis set, last observation
`carried forward, treatment naïve ................................................................................................... 44
`Table 23: Adjusted mean change in diastolic blood pressure – full analysis set, last observation
`carried forward, treatment naive ................................................................................................... 45
`Table 24: Rescue medication use – full analysis set, metformin patients .................................... 47
`Table 25: Odds ratio for rescue medication use – full analysis set, logistic regression, metformin
`patients .......................................................................................................................................... 48
`Table 26: Rescue medication use – full analysis set, treatment naive .......................................... 48
`Table 27: Odds ratio of rescue medication use – logistic regression, full analysis set, treatment
`naïve .............................................................................................................................................. 49
`
`Reference ID: 3694050
`
`
`6
`
`

`

`NDA-206073 (Empagliflozin/Linagliptin)
`Initial NDA Submission
`Clinical Review and Cross-Discipline Team Leader Review
`Reviewer: William H. Chong
`
`Table 28: Adjusted mean change in HbA1c by baseline HbA1c subgroup – full analysis set, last
`observation carried forward, metformin patients .......................................................................... 51
`Table 29: Adjusted mean change in HbA1c by baseline HbA1c subgroup – full analysis set, last
`observation carried forward, treatment naïve ............................................................................... 52
`Table 30: Adjusted mean change in HbA1c by age subgroup – full analysis set, last observation
`carried forward, metformin patients ............................................................................................. 55
`Table 31: Adjusted mean change in HbA1c by age subgroup – full analysis set, last observation
`carried forward, treatment naïve ................................................................................................... 56
`Table 32: Adjusted mean change in HbA1c by baseline renal function using estimated
`glomerular filtration rate by modification of diet in renal disease formula– full analysis set, last
`observation carried forward, metformin patients .......................................................................... 58
`Table 33: Adjusted mean change in HbA1c by baseline renal function using estimated
`glomerular filtration rate by modification of diet in renal disease formula– full analysis set, last
`observation carried forward, treatment naive ............................................................................... 59
`Table 34: Adjusted mean change in HbA1c from baseline by region – 24 weeks, full analysis set,
`last observation carried forward, analysis of covariance model, metformin patients ................... 61
`Table 35: Adjusted mean change in HbA1c from baseline by region – 24 weeks, full analysis set,
`last observation carried forward, analysis of covariance model, treatment naive ........................ 62
`Table 36: Change in HbA1c from baseline to 52 weeks – full analysis set, last observation
`carried forward, analysis of covariance model, metformin patients ............................................. 64
`Table 37: Reduction in HbA1c with fixed dose combination product compared to the individual
`components – 52 weeks, full analysis set, last observation carried forward, analysis of covariance
`model, metformin patients ............................................................................................................ 64
`Table 38: Change in HbA1c from baseline to 52 weeks – full analysis set, last observation
`carried forward, analysis of covariance model, treatment naïve .................................................. 65
`Table 39: Reduction in HbA1c with fixed dose combination product compared to the individual
`components – 52 weeks, full analysis set, last observation carried forward, analysis of covariance
`model, treatment naïve .................................................................................................................. 65
`Table 40: Analysis sets ................................................................................................................. 66
`Table 41: Exposure to randomized study drug – treated set, metformin background .................. 70
`Table 42: Baseline demographics – full analysis set, metformin patients .................................... 71
`Table 43: Exposure to randomized study drug – treated set, treatment naive .............................. 72
`Table 44: Baseline demographics – full analysis set, treatment naïve ......................................... 73
`Table 45: Patient deaths ................................................................................................................ 75
`Table 46: Treatment emergent nonfatal serious adverse events – treated set ............................... 79
`Table 47: Non-fatal serious adverse events reported in the 4 month safety update ..................... 82
`Table 48: Premature discontinuation of study drug and premature discontinuation from study at
`24 and 52 weeks – treated set, metformin patients and treatment naive ....................................... 84
`Table 49: Discontinuation of study drug due to an adverse event – treated set ............................ 84
`Table 50: Patients with significant adverse events – treated set, metformin patients ................... 86
`
`Reference ID: 3694050
`
`
`7
`
`

`

`NDA-206073 (Empagliflozin/Linagliptin)
`Initial NDA Submission
`Clinical Review and Cross-Discipline Team Leader Review
`Reviewer: William H. Chong
`
`Table 51: Listing of patients with significant adverse events including date of onset and
`associated preferred term – treated set, metformin patients ......................................................... 86
`Table 52: Patients with significant adverse events – treated set, treatment naïve ........................ 87
`Table 53: Listing of patients with significant adverse events including date of onset and
`associated preferred term – treated set, treatment naïve ............................................................... 87
`Table 54: Frequency of volume depletion events – treated set, pooled ........................................ 98
`Table 55: Frequency of volume depletion events – treated set, metformin patients .................... 99
`Table 56: Frequency of volume depletion events – treated set, treatment naïve ........................ 100
`Table 57: Patients with renal events – treated set, metformin patients ....................................... 105
`Table 58: Mean change in laboratory parameters of renal function – treated set, metformin
`patients ........................................................................................................................................ 106
`Table 59: Mean change in laboratory parameters of renal function – treated set, treatment naive
`..................................................................................................................................................... 107
`Table 60: Patients with hepatic events – treated set, metformin patients ................................... 102
`Table 61: Frequency of elevated liver enzymes – treated set, metformin patients ..................... 103
`Table 62: Patients with hepatic events – treated set, treatment naïve ......................................... 103
`Table 63: Frequency of elevated liver enzymes – treated set, treatment naïve .......................... 104
`Table 64: Incidence of urinary tract infections based on a customized MedDRA query – treated
`set, metformin patients, 52 weeks ................................................................................................. 91
`Table 65: Incidence urinary tract infections based on a customized MedDRA query – treated set,
`treatment naïve, 52 weeks ............................................................................................................. 93
`Table 66: Incidence of genital infections based on a customized MedDRA query – treated set,
`metformin patients ........................................................................................................................ 95
`Table 67: Incidence of genital infections based on a customized MedDRA query – treated set,
`treatment naïve .............................................................................................................................. 97
`Table 68: Frequency of malignancy events based on standardized MedDRA query – treated set
`..................................................................................................................................................... 101
`Table 69: Frequency of hypoglycemic events – metformin patients, treated set .......................... 89
`Table 70: Time to first confirmed hypoglycemic episode – metformin patients, treated set ....... 90
`Table 71: Frequency of hypoglycemic events – treatment naïve, treated set ............................... 90
`Table 72: Time to first confirmed hypoglycemic episode – treatment naive, treated set ............. 91
`Table 73: Incidence of treatment emergent pancreatitis and increased lipase – treated set ....... 110
`Table 74: Incidence of hypersensitivity reactions – treated set .................................................. 108
`Table 75: Cardiovascular events – treated set, metformin patients ............................................ 111
`Table 76: Cardiovascular events – treated set, treatment naive .................................................. 111
`Table 77: Treatment emergent adverse events occurring in ≥ 10% of patients by system organ
`class from either fixed dose combination arm by system organ class– treated set, metformin
`patients ........................................................................................................................................ 116
`
`Reference ID: 3694050
`
`
`8
`
`

`

`NDA-206073 (Empagliflozin/Linagliptin)
`Initial NDA Submission
`Clinical Review and Cross-Discipline Team Leader Review
`Reviewer: William H. Chong
`
`Table 78: Treatment emergent adverse events reported in ≥ 2% of patients by preferred term and
`more commonly with the fixed dose combination that are not presented in Table 77 – treated set,
`metformin patients ...................................................................................................................... 118
`Table 79: Treatment emergent adverse events occurring in ≥ 10% of patients by system organ
`class from either fixed dose combination arm by system organ class – treated set, treatment naive
`..................................................................................................................................................... 119
`Table 80: Treatment emergent adverse events reported in ≥ 2% of patients by preferred term and
`more commonly with the fixed dose combination that are not presented in Table 79 – treated set,
`metformin patients ...................................................................................................................... 121
`Table 81: Categorical shifts in serum bicarbonate – 52 weeks, treated set, metformin patients 124
`Table 82: Categorical shifts in serum bicarbonate – 52 weeks, treated set, treatment naïve ...... 125
`Table 83: Change in median serum lipase – 52 weeks, treated set, metformin patients ............ 126
`Table 84: Categorical shifts in serum lipase – 52 weeks, treated set, metformin patients ......... 126
`Table 85: Change in serum lipase – 52 weeks, treated set, treatment naïve ............................... 127
`Table 86: Categorical shifts in serum lipase – 52 weeks, treated set, treatment naïve ............... 127
`Table 87: Change in hematocrit – 52 weeks, treated set, metformin patients ............................ 128
`Table 88: Categorical shifts in hematocrit – 52 weeks, treated set, metformin patient .............. 129
`Table 89: Change in hematocrit – 52 weeks, treated set, treatment naïve .................................. 130
`Table 90: Categorical shifts in hematocrit – 52 weeks, treated set, treatment naïve .................. 130
`Table 91: Change in lipid parameters – 52 weeks, treated set, metformin patients ................... 132
`Table 92: Change in lipid parameters –